Alcohol and Sca-1; Impairment of the granulopoietic precursor cell response

描述（由申请人提供）： 项目摘要/摘要：酒精滥用易使宿主感染细菌。严重细菌感染的酒精滥用者的一个突出特点是他们经常出现粒细胞减少症，这是死亡率增加的一个指标。粒细胞代表体循环中最大的吞噬细胞群体，构成宿主防御入侵病原体的第一道防线。为了应对细菌感染，骨髓增加粒细胞的产生，以加强宿主对入侵病原体的防御。在此过程中，原始造血前体细胞被重新编程，以使其谱系向粒细胞生成转化。我们最近的研究表明，在败血症期间，骨髓lin-cKit+Sca-1+细胞（LKS细胞，富集的造血干细胞群体）的数量迅速增加。这种LKS细胞反应主要由Sca-1表达的上调支持，Sca-1表达对于粒细胞产生的增强至关重要。酒精中毒会削弱这种反应。我对这一应用的初步研究表明，Sca-1在败血症期间的表达也在表达低水平粒细胞分化抗原-1（Gr 1）的下游粒细胞系定型细胞中增强。Sca-1在该定型细胞区室中的上调表达与粒细胞生成前体的增殖增强和粒细胞的加速产生相关。该过程涉及下调STAT 3信号传导和增强p44/p42-细胞周期蛋白D信号传导的关键细胞信号传导途径。酒精中毒破坏了细胞信号传导活性的这些调节，并通过未知机制损害了Sca-1相关的粒细胞产生的增强。基于这些初步的研究，我的假设是，酒精损害Sca-1信号在粒细胞发育的早期阶段，并阻止粒细胞对败血症的反应。两个具体目标是：（1）检验酒精损害Sca-1介导的p44/42-细胞周期蛋白D信号在败血症期间促进Gr 1 lo细胞增殖的增强的预测;（2）检验酒精破坏Sca-1介导的STAT 3信号在败血症期间调节Gr 1 lo细胞增殖的下调的预测。这项研究将提供新的信息的分子机制，酒精诱导的损害的粒细胞对细菌感染的反应。它也将为开发有效的治疗策略以治疗严重细菌感染的酒精滥用者的骨髓抑制奠定基础。

DESCRIPTION (provided by applicant): Project Summary/Abstract: Alcohol abuse predisposes the host to bacterial infections. A prominent feature of alcohol abusers with severe bacterial infection is that they frequently present with granulocytopenia, which is an indicator of increased mortality. Representing the largest population of phagocytes in the systemic circulation, granulocytes constitute the first line of host defense against invading pathogens. In response to bacterial infection, the bone marrow increases granulocyte production in order to reinforce host defense against invading pathogens. During this process, primitive hematopoietic precursor cells are reprogrammed to polarize their lineage commitment toward granulopoiesis. Our recent studies have revealed that the number of bone marrow lin-cKit+Sca-1+ cells (LKS cells, a population of enriched hematopoietic stem cells) is rapidly increased during septicemia. This LKS cell response is primarily supported by the up-regulation of Sca-1 expression, which is critical for the enhancement of granulocyte production. Alcohol intoxication impairs this response. My preliminary studies for this application show that Sca-1 expression during septicemia is also enhanced in downstream granulocyte lineage committed cells that express low levels of granulocyte differentiation antigen- 1 (Gr1). The up-regulated expression of Sca-1 in this committed cell compartment is associated with enhanced proliferation of granulopoietic precursors and accelerated production of granulocytes. This process involves key cell signaling pathways that down-regulate STAT3 signaling and enhance p44/p42-cyclin D signaling. Alcohol intoxication disrupts these adjustments in cell signaling activity and impairs Sca-1 associated enhancement of granulocyte production by an unknown mechanism. Based on these preliminary studies, my hypothesis is that alcohol impairs Sca-1 signaling in the early stage of granulocyte development and blocks the granulopoietic response to septicemia. Two specific aims are: (1) To test the prediction that alcohol impairs Sca-1 mediated enhancement of p44/42-cyclin D signaling in promoting Gr1lo cell proliferation during septicemia; (2) To test the prediction that alcohol disrupts Sca-1 mediated down- regulation of STAT3 signaling in the regulation of Gr1lo cell proliferation during septicemia. This study will provide novel information about the molecular mechanism underlying alcohol-induced impairment of the granulopoietic response to bacterial infection. It will also build a foundation for developing effective therapeutic strategies to treat myelosuppression in alcohol abusers with severe bacterial infection.